Division of Allergy and Immunology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Mucosal Immunol. 2021 Nov;14(6):1271-1281. doi: 10.1038/s41385-021-00416-4. Epub 2021 Aug 2.
Expression of Ikaros family transcription factor IKZF3 (Aiolos) increases during murine eosinophil lineage commitment and maturation. Herein, we investigated Aiolos expression and function in mature human and murine eosinophils. Murine eosinophils deficient in Aiolos demonstrated gene expression changes in pathways associated with granulocyte-mediated immunity, chemotaxis, degranulation, ERK/MAPK signaling, and extracellular matrix organization; these genes had ATAC peaks within 1 kB of the TSS that were enriched for Aiolos-binding motifs. Global Aiolos deficiency reduced eosinophil frequency within peripheral tissues during homeostasis; a chimeric mouse model demonstrated dependence on intrinsic Aiolos expression by eosinophils. Aiolos deficiency reduced eosinophil CCR3 surface expression, intracellular ERK1/2 signaling, and CCL11-induced actin polymerization, emphasizing an impaired functional response. Aiolos-deficient eosinophils had reduced tissue accumulation in chemokine-, antigen-, and IL-13-driven inflammatory experimental models, all of which at least partially depend on CCR3 signaling. Human Aiolos expression was associated with active chromatin marks enriched for IKZF3, PU.1, and GATA-1-binding motifs within eosinophil-specific histone ChIP-seq peaks. Furthermore, treating the EOL-1 human eosinophilic cell line with lenalidomide yielded a dose-dependent decrease in Aiolos. These collective data indicate that eosinophil homing during homeostatic and inflammatory allergic states is Aiolos-dependent, identifying Aiolos as a potential therapeutic target for eosinophilic disease.
Ikaros 家族转录因子 IKZF3（Aiolos）的表达在小鼠嗜酸性粒细胞谱系的分化和成熟过程中增加。在此，我们研究了 Aiolos 在成熟的人和鼠嗜酸性粒细胞中的表达和功能。缺乏 Aiolos 的小鼠嗜酸性粒细胞表现出与粒细胞介导的免疫、趋化性、脱颗粒、ERK/MAPK 信号和细胞外基质组织相关的途径中的基因表达变化；这些基因在 TSS 附近 1kb 内具有 ATAC 峰，富含 Aiolos 结合基序。在稳态期间，Aiolos 缺乏会降低外周组织中的嗜酸性粒细胞频率；嵌合小鼠模型表明嗜酸性粒细胞对固有 Aiolos 表达的依赖性。Aiolos 缺乏会降低嗜酸性粒细胞 CCR3 表面表达、细胞内 ERK1/2 信号和 CCL11 诱导的肌动蛋白聚合，强调了功能反应受损。在趋化因子、抗原和 IL-13 驱动的炎症实验模型中，Aiolos 缺陷型嗜酸性粒细胞的组织积累减少，所有这些模型至少部分依赖于 CCR3 信号。人 Aiolos 的表达与活性染色质标记相关，这些标记在嗜酸性粒细胞特异性组蛋白 ChIP-seq 峰中富集了 IKZF3、PU.1 和 GATA-1 结合基序。此外，用来那度胺处理 EOL-1 人嗜酸性细胞系可导致 Aiolos 呈剂量依赖性下降。这些综合数据表明，在稳态和炎症过敏状态下，嗜酸性粒细胞归巢依赖于 Aiolos，这表明 Aiolos 是嗜酸性粒细胞疾病的潜在治疗靶点。
